Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins.
Proteinaceous cast formation in the distal nephron of the kidney from low molecular weight proteinuria is a significant, but poorly characterized, cause of renal failure. To study this phenomenon, we: (a) microperfused the loop segment (LS) of rats in vivo with artificial tubule fluid (ATF) containing four different low molecular weight proteins, 0.01-50 mg/ml, to detect alterations in LS function, and (b) examined the interaction between several proteins and Tamm-Horsfall glycoprotein (THP) in vitro with turbidity and dynamic light-scattering measurements. Perfusion of the LS for less than 2 min with cast-forming proteins (Bence Jones protein [BJP3] and myoglobin) decreased chloride absorption and elevated early distal tubule fluid (ED) [Cl-], compared with results obtained with control perfusions that used ATF alone. BJP3 decreased chloride absorption in a concentration-dependent fashion. Perfusion with non-cast-forming proteins (albumin and BJP1) enhanced chloride absorption and decreased ED [Cl-]. In vitro, proteins that had isoelectric points (pI) greater than 5.1 aggregated with THP. Aggregation was enhanced with increasing [NaCl] or [CaCl2]. Albumin (pI 4.8) and beta-lactoglobulin (pI 5.1) did not coprecipitate. The molecular size of THP alone increased when [NaCl] greater than 80 mM. Thus, cast-forming proteins aggregated with THP in vitro and caused in vivo LS dysfunction, which elevated ED [Cl-], facilitating aggregation. In contrast, non-cast-forming proteins either did not interact with THP or lowered ED [Cl-], which did not provide an environment for aggregation. Altered LS function and interaction of some proteins with THP were related to different physicochemical properties of the proteins and independently contributed to the formation of proteinaceous casts in the kidney.
Sanders
P W
PW
Department of Medicine, University of Alabama, Birmingham 35294.
Booker
B B
BB
Bishop
J B
JB
Cheung
H C
HC
D000818:Animals; D002712:Chlorides / Q000378:metabolism; D006801:Humans; D007526:Isoelectric Point; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology; D008027:Light; D008297:Male; D009088:Mucoproteins / Q000378:metabolism; D009391:Nephelometry and Turbidimetry; D010477:Perfusion; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012542:Scattering, Radiation; D058949:Uromodulin
D002712:Chlorides; D009088:Mucoproteins; D011506:Proteins; C548612:UMOD protein, human; D058949:Uromodulin